The proposal outlines a 5-year training plan to facilitate Dr. Pepperell's career development as an academic Physician scientist. Dr. Pepperell recently completed clinical training in infectious diseases at Stanford University. The proposed project takes advantage of outstanding technical and intellectual resources available at Stanford for the study of M. tuberculosis. Drs. Gary Schoolnik and Peter Small will serve as co-mentors for the project. Dr. Schoolnik is an internationally recognized authority on the molecular biology and pathogenesis of TB, while Dr. Small has an equally successful research program focused on the evolutionary genetics of M.TB. The candidate proposes to acquire training in bacterial population genetics in order to examine currently unexplained aspects of TB epidemics from the perspective of the pathogen. TB epidemics have historically declined in a stereotypical manner despite variable host populations, treatment and environmental conditions. The hypothesis under study relates the degree of genetic diversity seen within a population of TB organisms to the stage of the disease epidemic in the host population. We hypothesize that genetic diversity increases over time and that biologically important changes in the organism either cause or accompany the natural decline of disease epidemics. Through collaboration with Canadian public health authorities, the candidate has access to a unique dataset which will allow her to examine this hypothesis. Clinical data and archived TB strains are available from 2 well defined populations of Native Canadians which experienced TB epidemics 70 years apart. The candidate proposes to use TB genotyping techniques to create a micro-phylogeny of TB isolates from these communities. The aims are to: 1) reconstruct the evolutionary events which occurred over the course of these epidemics 2) define the strain types which predominate at the initiation versus the conclusion of an epidemic and 3) quantify the amount of diversity generated over the course of an epidemic. The study communities are geographically and socially isolated and there is an opportunity to study the evolution of a small number of TB strains, without the confounding effect of migration. Ultimately, this study should provide insight into the ways in which TB bacteria evolve to avoid attack by the human immune system, drugs and vaccines. An understanding of this evolution would help to develop better treatments for a disease which kills almost 3 million people per year.